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1.  Predicting Inhaled Corticosteroid Response in Asthma with Two Associated SNPs 
The pharmacogenomics journal  2012;13(4):306-311.
Inhaled corticosteroids are the most commonly used controller medications prescribed for asthma. Two single-nucleotide polymorphisms (SNPs), rs1876828 in CRHR1 and rs37973 in GLCCI1, have previously been associated with corticosteroid efficacy. We studied data from four existing clinical trials of asthmatics who received inhaled corticosteroids and had lung function measured by forced expiratory volume in one second (FEV1) before and after the period of such treatment. We combined the two SNPs rs37973 and rs1876828 into a predictive test of FEV1 change using a Bayesian model, which identified patients with good or poor steroid response (highest or lowest quartile, respectively) with predictive performance of 65.7% (p = 0.039 vs. random) area under the receiver-operator characteristic curve in the training population and 65.9% (p = 0.025 vs. random) in the test population. These findings show that two genetic variants can be combined into a predictive test that achieves similar accuracy and superior replicability compared with single SNP predictors.
doi:10.1038/tpj.2012.15
PMCID: PMC3434304  PMID: 22641026
Pharmacogenetics; Asthma; Glucocorticoids; Predictive Modeling
2.  Modeling Asthma Exacerbations Through Lung Function in Children 
Background
Formal economic evaluation using a model-based approach is playing an increasingly important role in healthcare decision making.
Objective
To develop a model using an objective measure of lung function, prebronchodilator forced expiratory volume in 1 second as a percent of predicted (FEV1% predicted), as the primary independent factor to predict the frequency of adverse events related to exacerbation of asthma on a population level.
Methods
We developed a Markov simulation model of childhood asthma using data from the Childhood Asthma Management Program (CAMP). The primary outcomes were the result of asthma exacerbations defined as: hospitalizations, emergency department (ED) visits, and the need for oral corticosteroid therapy. Predicted monthly frequencies for each acute event were based on negative binomial regression equations estimated from the placebo arm of CAMP with covariates of age, prebronchodilator FEV1% predicted, time in study, prior hospitalizations, and prior nocturnal awakenings.
Results
Simulated versus observed mean number of acute events were similar within the placebo and treatment groups. While the trial demonstrated treatment effects of 48% reduction in hospitalizations, 46% reduction in ED visits, and 44% reduction in the need for oral corticosteroid therapy at 48 months; the model simulated similar reductions of 49% in hospitalizations, 41% in ED visits, and 46% in the need for oral corticosteroid therapy.
Conclusion
Our findings suggest that longitudinal intervention effects may be modeled through FEV1% predicted to estimate hospitalizations, ED visits, and need for oral corticosteroid therapy in childhood asthma for planning and evaluation purposes.
doi:10.1016/j.jaci.2012.08.009
PMCID: PMC3683131  PMID: 23021884
asthma; pediatric patients; lung function; FEV percent predicted; hospitalizations; emergency department visits; model
3.  Effect of Vitamin D and Inhaled Corticosteroid Treatment on Lung Function in Children 
Rationale: Low vitamin D levels are associated with asthma and decreased airway responsiveness. Treatment with inhaled corticosteroids improves airway responsiveness and asthma control.
Objectives: To assess the effect of vitamin D levels on prebronchodilator FEV1, bronchodilator response, and responsiveness to methacholine (PC20, provocative concentration of methacholine producing a 20% decline in FEV1) in patients with asthma treated with inhaled corticosteroids.
Methods: We measured 25-hydroxyvitamin D levels in the serum of children with persistent asthma at the time of enrollment in the Childhood Asthma Management Program. We divided subjects into the vitamin D sufficiency (>30 ng/ml), insufficiency (20–30 ng/ml), and deficiency (<20 ng/ml) groups. Covariates included age, treatment, sex, body mass index, race, history of emergency department visits, hospitalizations, and season that vitamin D specimen was drawn. Our main outcome measures were change in prebronchodilator FEV1, bronchodilator response, and PC20 from enrollment to 8–12 months.
Measurements and Main Results: Of the 1,024 subjects, 663 (65%) were vitamin D sufficient, 260 (25%) were insufficient, and 101 (10%) were deficient. Vitamin D–deficient subjects were more likely to be older, African American, and have a higher body mass index compared with the vitamin D–sufficient and insufficient subjects. In the inhaled corticosteroid treatment group, prebronchodilator FEV1 increased from randomization to 12 months by 140 ml in the vitamin D–deficient group and prebronchodilator FEV1 increased by 330 ml in the vitamin D insufficiency group and by 290 ml in the vitamin D sufficiency group (P = 0.0072), in adjusted models.
Conclusions: In children with asthma treated with inhaled corticosteroids, vitamin D deficiency is associated with poorer lung function than in children with vitamin D insufficiency or sufficiency.
doi:10.1164/rccm.201202-0351OC
PMCID: PMC3480528  PMID: 22798322
asthma; vitamin D; lung function; forced expiratory volume; children
4.  How Can We Communicate About Vaccines With Adolescents and Their Parents? 
Clinical pediatrics  2010;49(4):373-380.
Objective
To describe parents’ and adolescents’ perceptions about vaccination.
Methods
Qualitative interviews of 22 mothers/grandmothers and 25 10- to 14-year-olds.
Results
Themes emerged in 3 focus areas. (a) Understanding: Both adults and adolescents had difficulty understanding concepts of risks, benefits, prevention, and vaccination. (b) Decision making: Adults saw vaccination as an opportunity to help their adolescent develop skills for transition to adulthood. Adolescents worried about being lied to (reinforced by being told “it won’t hurt”), physical pain, and cleanliness. (c) Preventing sexually transmitted infections: Adults were divided between those who felt their child would not need such a vaccine and those who wanted to “be safe” to protect their child in the future.
Conclusions
At the same time that even basic concepts about vaccination should be explained to both adults and adolescents, adolescence represents a time for learning about responsible decision making. Discussion regarding the risks and benefits of vaccines can be part of transitioning to adult decision making.
doi:10.1177/0009922809351091
PMCID: PMC3773171  PMID: 20118100
5.  Development of a Pharmacogenetic Predictive Test in asthma: proof of concept 
Pharmacogenetics and genomics  2010;20(2):86-93.
Objective
To assess the feasibility of developing a Combined Clinical and Pharmacogenetic Predictive Test, comprised of multiple single nucleotide polymorphisms (SNPs) that is associated with poor bronchodilator response (BDR).
Methods
We genotyped SNPs that tagged the whole genome of the parents and children in the Childhood Asthma Management Program (CAMP) and implemented an algorithm using a family-based association test that ranked SNPs by statistical power. The top eight SNPs that were associated with BDR comprised the Pharmacogenetic Predictive Test. The Clinical Predictive Test was comprised of baseline forced expiratory volume in 1 s (FEV1). We evaluated these predictive tests and a Combined Clinical and Pharmacogenetic Predictive Test in three distinct populations: the children of the CAMP trial and two additional clinical trial populations of asthma. Our outcome measure was poor BDR, defined as BDR of less than 20th percentile in each population. BDR was calculated as the percent difference between the prebronchodilator and postbronchodilator (two puffs of albuterol at 180 μg/puff) FEV1 value. To assess the predictive ability of the test, the corresponding area under the receiver operating characteristic curves (AUROCs) were calculated for each population.
Results
The AUROC values for the Clinical Predictive Test alone were not significantly different from 0.50, the AUROC of a random classifier. Our Combined Clinical and Pharmacogenetic Predictive Test comprised of genetic polymorphisms in addition to FEV1 predicted poor BDR with an AUROC of 0.65 in the CAMP children (n= 422) and 0.60 (n= 475) and 0.63 (n= 235) in the two independent populations. Both the Combined Clinical and Pharmacogenetic Predictive Test and the Pharmacogenetic Predictive Test were significantly more accurate than the Clinical Predictive Test (AUROC between 0.44 and 0.55) in each of the populations.
Conclusion
Our finding that genetic polymorphisms with a clinical trait are associated with BDR suggests that there is promise in using multiple genetic polymorphisms simultaneously to predict which asthmatics are likely to respond poorly to bronchodilators.
doi:10.1097/FPC.0b013e32833428d0
PMCID: PMC3654515  PMID: 20032818
asthma; bronchodilator response; personalized medicine; pharmacogenetic test; predictive medicine
6.  Acceptance of Asthma Pharmacogenetic Study by Children and Adults 
Background
Pharmacogenetic testing may change clinical medicine by allowing clinicians to tailor medications based on a patient’s genetic makeup, however, these tests must first be validated in large, real-life populations of subjects that include children. A dearth of knowledge exists for whether pediatric populations are as willing as adult populations to provide samples for such studies.
Objective
(1) To assess whether pediatric and adult patients with persistent asthma are willing to provide specimens for DNA extraction and genetic studies. (2) To assess whether patients’ willingness to provide blood as compared to buccal smear specimens differ.
Methods
Of 644 patients ages 4–38 years who had three or more prescription fills for inhaled corticosteroids in one year, 60% (385) were randomized to the blood specimen group and 40% (259) were randomized to the buccal smear group in order to study acceptance of different biospecimen collection methods. Research assistants contacted subjects to obtain consent, perform a phone survey, and request a specimen.
Results
There were no baseline differences between subjects randomized to the blood specimen group versus buccal smear group with respect to age, gender, or number of dispensings of inhaled corticosteroids. Of 259 subjects in the buccal smear group, 30% (78) provided samples, and of 385 subjects in the blood specimen group, 16% (60) provided samples. Subjects randomized to the buccal smear group were more likely to provide specimens for genetic study compared to subjects randomized to the blood specimen group (RR 1.21; 95% CI 1.10 – 1.32), even after adjusting for age. Pediatric subjects were more likely to provide specimens for genetic study than adult subjects with 23% (113) of pediatric subjects providing samples and 15% (25) of adult subjects providing samples (p=0.03).
Conclusion
Children with asthma are as likely to participate in genetic studies as adults. Both children and adult subjects are more likely to provide buccal smear specimens rather than blood specimens for genetic study.
doi:10.4172/2153-0645.1000103
PMCID: PMC3614400  PMID: 23560243
pharmacogenetics; patient recruitment; children; buccal swab; blood specimen
7.  Racial/Ethnic Variation in Parent Perceptions of Asthma 
Objective
Black and Latino children with asthma have worse morbidity and receive less controller medication than their white peers. Scant information exists on racial/ethnic differences in parent perceptions of asthma. To compare parent perceptions among black, Latino, and white children with asthma in 4 domains: (1) expectations for functioning with asthma; (2) concerns about medications; (3) interactions with providers; and (4) competing family priorities.
Methods
In this cross-sectional study, we conducted telephone interviews with parents of children with persistent asthma in a Medicaid health plan and a multispecialty provider group in Massachusetts. To measure expectations for functioning and other domains, we adapted multi-item scales from past studies. Associations between race/ethnicity and these domains were evaluated in multivariate analyses that controlled for age, gender, household income, parental education, insurance, and language. The response rate was 72%.
Results
Of the 739 study children, 24% were black, 21% Latino, and 43% white. Parents of black and Latino children had lower expectations for their children’s functioning with asthma (P < .001), higher levels of worry about their children’s asthma (P < .001), and more competing family priorities (P = 004) compared with parents of white children. Parents of Latino children had higher levels of concern about medications for asthma than parents of black or white children (P = 002). There were no differences among racial/ethnic groups in reports of interactions with the provider of their children’s asthma care.
Conclusions
Efforts to eliminate disparities in childhood asthma may need to address variation in expectations and competing priorities between minority and white families.
doi:10.1016/j.ambp.2007.10.007
PMCID: PMC3614412  PMID: 18355737
asthma; health care disparities; racial/ethnic variation
8.  Cost-effectiveness of omalizumab in adults with severe asthma: Results from the Asthma Policy Model 
Background
Omalizumab (trade name Xolair) is approved by the US Food and Drug Administration for treatment of moderate-to-severe allergic asthma. Given the high acquisition cost of omalizumab, its role and cost-effectiveness in disease management require definition.
Objective
We sought to identify the clinical and economic circumstances under which omalizumab might or might not be a cost-effective option by using a mathematic model.
Methods
We merged published data on clinical and economic outcomes (including acute event incidence, frequency/severity of hospitalizations, and health-related quality of life) to project 10-year costs, quality-adjusted life years (QALYs), and cost-effectiveness of treatment with omalizumab in addition to inhaled corticosteroids. Sensitivity analyses were conducted by using input data ranges from a variety of sources (published clinical trials and observational databases).
Results
For patients with baseline acute event rates, omalizumab conferred an additional 1.7 quality-adjusted months at an incremental cost of $131,000 over a 10-year planning horizon, implying a cost-effectiveness ratio of $821,000 per QALY gained. For patients with 5 times the baseline acute event rate, the cost-effectiveness ratio was $491,000 per QALY gained. The projected cost-effectiveness ratio could fall within a range of other programs that are widely considered to be cost-effective if the cost of omalizumab decreases to less than $200.
Conclusion
Omalizumab is not cost-effective for most patients with severe asthma. The projected cost-effectiveness ratios could fall within a favorable range if the cost of omalizumab decreases significantly.
Clinical implications
Based on the high cost of omalizumab, it is especially important that clinicians explore alternative medications for asthma before initiating omalizumab.
doi:10.1016/j.jaci.2007.07.055
PMCID: PMC3476046  PMID: 17904628
Omalizumab; cost-effectiveness; asthma; anti-IgE
9.  Propensity Score-based Sensitivity Analysis Method for Uncontrolled Confounding 
American Journal of Epidemiology  2011;174(3):345-353.
The authors developed a sensitivity analysis method to address the issue of uncontrolled confounding in observational studies. In this method, the authors use a 1-dimensional function of the propensity score, which they refer to as the sensitivity function (SF), to quantify the hidden bias due to unmeasured confounders. The propensity score is defined as the conditional probability of being treated given the measured covariates. Then the authors construct SF-corrected inverse-probability-weighted estimators to draw inference on the causal treatment effect. This approach allows analysts to conduct a comprehensive sensitivity analysis in a straightforward manner by varying sensitivity assumptions on both the functional form and the coefficients in the 1-dimensional SF. Furthermore, 1-dimensional continuous functions can be well approximated by low-order polynomial structures (e.g., linear, quadratic). Therefore, even if the imposed SF is practically certain to be incorrect, one can still hope to obtain valuable information on treatment effects by conducting a comprehensive sensitivity analysis using polynomial SFs with varying orders and coefficients. The authors demonstrate the new method by implementing it in an asthma study which evaluates the effect of clinician prescription patterns regarding inhaled corticosteroids for children with persistent asthma on selected clinical outcomes.
doi:10.1093/aje/kwr096
PMCID: PMC3202161  PMID: 21659349
confounding factors (epidemiology); inverse probability weighting; propensity score; sensitivity analysis; sensitivity function; uncontrolled confounding
10.  Genome-Wide Association Analysis in Asthma Subjects Identifies SPATS2L as a Novel Bronchodilator Response Gene 
PLoS Genetics  2012;8(7):e1002824.
Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV1) before and after the administration of a short-acting β2-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of β2-agonist efficacy. BDR is a complex trait that is partly under genetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV1 after administration of a β2-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: CAMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide polymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting for age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects from DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. The lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary analysis, those with rs295137 TT genotype had a median BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased β2-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of β2-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to β2-agonists through GWAS.
Author Summary
Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function before and after the administration of short-acting β2-agonists, common medications used for asthma treatment. We performed a genome-wide association study of BDR with 1,644 white asthmatic subjects from six drug clinical trials and attempted to replicate these findings in 1,051 white subjects from two independent cohorts. The most significant associated variant was near the SPATS2L gene. We knocked down SPATS2L mRNA in human airway smooth muscle cells and found that β2-adrenergic receptor levels increased, suggesting that SPATS2L may be a regulator of BDR. Our results highlight the promise of pursuing GWAS results that do not necessarily reach genome-wide significance and are an example of how results from pharmacogenetic GWAS can be studied functionally.
doi:10.1371/journal.pgen.1002824
PMCID: PMC3390407  PMID: 22792082
11.  Postpartum Mothers’ Attitudes, Knowledge, and Trust Regarding Vaccination 
Maternal and Child Health Journal  2007;12(6):766-773.
Objective
To examine attitudes and knowledge about vaccinations in postpartum mothers.
Methods
This cross-sectional study collected data via written survey to postpartum mothers in a large teaching hospital in Connecticut. We used multivariable analysis to identify mothers who were less trusting with regard to vaccines.
Results
Of 228 mothers who participated in the study, 29% of mothers worried about vaccinating their infants: 23% were worried the vaccines would not work, 11% were worried the doctor would give the wrong vaccine, and 8% worried that “they” are experimenting when they give vaccines. Mothers reported that the most important reasons to vaccinate were to prevent disease in the baby (74%) and in society (11%). Knowledge about vaccination was poor; e.g., 33% correctly matched chicken pox with varicella vaccine. Mothers who were planning to breastfeed (P = .01), were primiparous (P = .01), or had an income <$40,000 but did not receive support from the women, infants, and children (WIC) program were less trusting with regard to vaccines (P = .03). Although 70% wanted information about vaccines during pregnancy, only 18% reported receiving such information during prenatal care.
Conclusion
Although the majority of infants receive vaccines, their mothers have concerns and would like to receive immunization information earlier. Mothers who are primiparous, have low family incomes but do not qualify for the WIC program, or are breastfeeding may need special attention to develop a trusting relationship around vaccination. Mothers would benefit from additional knowledge regarding the risks and benefits of vaccines particularly during prenatal care.
doi:10.1007/s10995-007-0302-4
PMCID: PMC3344281  PMID: 17987370
Vaccinations; Mothers; Attitudes; Trust; Postpartum period
12.  Fungal Exposure Modulates the Effect of Polymorphisms of Chitinases on Emergency Department Visits and Hospitalizations 
Rationale: Chitinases are enzymes that cleave chitin, which is present in fungal cells. Two types of human chitinases, chitotriosidase and acidic mammalian chitinase, and the chitinase-like protein, YKL-40, seem to play an important role in asthma. We hypothesized that exposure to environmental fungi may modulate the effect of chitinases in individuals with asthma.
Objectives: To explore whether interactions between high fungal exposure and common genetic variants in the two chitinases in humans, CHIT1 and CHIA, and the chitinase 3-like 1 gene, CHI3L1, are associated with severe asthma exacerbations and other asthma-related outcomes.
Methods: Forty-eight single nucleotide polymorphisms (SNPs) in CHIT1, CHIA, and CHI3L1 and one CHIT1 duplication were genotyped in 395 subjects and their parents as part of the Childhood Asthma Management Program. Household levels of mold (an index of fungal exposure) were determined on house dust samples. We conducted family-based association tests with gene–environment interactions. Our outcome was severe exacerbation, defined as emergency department visits and hospitalizations from asthma over a 4-year period, and our secondary outcomes included indices of lung function and allergy-related phenotypes.
Measurements and Main Results: Of the 395 subjects who had mold levels at randomization, 24% (95 subjects) had levels that were greater than 25,000 units per gram of house dust (high mold exposure). High mold exposure significantly modified the relation between three SNPs in CHIT1 (rs2486953, rs4950936, and rs1417149) and severe exacerbations (P for interaction 0.0010 for rs2486953, 0.0008 for rs4950936, and 0.0005 for rs1417149). High mold exposure did not significantly modify the relationship between any of the other variants and outcomes.
Conclusions: Environmental exposure to fungi, modifies the effect of CHIT1 SNPs on severe asthma exacerbations.
doi:10.1164/rccm.201003-0322OC
PMCID: PMC2970860  PMID: 20538957
chitinase; asthma; CHIA; CHIT1; CHI13L1
13.  Genome Wide Association Study to predict severe asthma exacerbations in children using random forests classifiers 
BMC Medical Genetics  2011;12:90.
Background
Personalized health-care promises tailored health-care solutions to individual patients based on their genetic background and/or environmental exposure history. To date, disease prediction has been based on a few environmental factors and/or single nucleotide polymorphisms (SNPs), while complex diseases are usually affected by many genetic and environmental factors with each factor contributing a small portion to the outcome. We hypothesized that the use of random forests classifiers to select SNPs would result in an improved predictive model of asthma exacerbations. We tested this hypothesis in a population of childhood asthmatics.
Methods
In this study, using emergency room visits or hospitalizations as the definition of a severe asthma exacerbation, we first identified a list of top Genome Wide Association Study (GWAS) SNPs ranked by Random Forests (RF) importance score for the CAMP (Childhood Asthma Management Program) population of 127 exacerbation cases and 290 non-exacerbation controls. We predict severe asthma exacerbations using the top 10 to 320 SNPs together with age, sex, pre-bronchodilator FEV1 percentage predicted, and treatment group.
Results
Testing in an independent set of the CAMP population shows that severe asthma exacerbations can be predicted with an Area Under the Curve (AUC) = 0.66 with 160-320 SNPs in comparison to an AUC score of 0.57 with 10 SNPs. Using the clinical traits alone yielded AUC score of 0.54, suggesting the phenotype is affected by genetic as well as environmental factors.
Conclusions
Our study shows that a random forests algorithm can effectively extract and use the information contained in a small number of samples. Random forests, and other machine learning tools, can be used with GWAS studies to integrate large numbers of predictors simultaneously.
doi:10.1186/1471-2350-12-90
PMCID: PMC3148549  PMID: 21718536
14.  Polymorphisms of Chitinases are not Associated with Asthma 
Short Summary
Despite the potential role of chitinases and chitinase-like proteins in the pathogenesis of asthma, variants in their respective genes are not associated with asthma, changes in lung physiology or allergy-related phenotypes in Caucasian children.
doi:10.1016/j.jaci.2009.12.995
PMCID: PMC2844863  PMID: 20226308
chitinase; chitinase-like protein; CHIA; CHIT1; CHI13L1; YKL-40; AMCase; SNPs; asthma
15.  A preconditioning nerve lesion inhibits mechanical pain hypersensitivity following subsequent neuropathic injury 
Molecular Pain  2011;7:1.
Background
A preconditioning stimulus can trigger a neuroprotective phenotype in the nervous system - a preconditioning nerve lesion causes a significant increase in axonal regeneration, and cerebral preconditioning protects against subsequent ischemia. We hypothesized that a preconditioning nerve lesion induces gene/protein modifications, neuronal changes, and immune activation that may affect pain sensation following subsequent nerve injury. We examined whether a preconditioning lesion affects neuropathic pain and neuroinflammation after peripheral nerve injury.
Results
We found that a preconditioning crush injury to a terminal branch of the sciatic nerve seven days before partial ligation of the sciatic nerve (PSNL; a model of neuropathic pain) induced a significant attenuation of pain hypersensitivity, particularly mechanical allodynia. A preconditioning lesion of the tibial nerve induced a long-term significant increase in paw-withdrawal threshold to mechanical stimuli and paw-withdrawal latency to thermal stimuli, after PSNL. A preconditioning lesion of the common peroneal induced a smaller but significant short-term increase in paw-withdrawal threshold to mechanical stimuli, after PSNL. There was no difference between preconditioned and unconditioned animals in neuronal damage and macrophage and T-cell infiltration into the dorsal root ganglia (DRGs) or in astrocyte and microglia activation in the spinal dorsal and ventral horns.
Conclusions
These results suggest that prior exposure to a mild nerve lesion protects against adverse effects of subsequent neuropathic injury, and that this conditioning-induced inhibition of pain hypersensitivity is not dependent on neuroinflammation in DRGs and spinal cord. Identifying the underlying mechanisms may have important implications for the understanding of neuropathic pain due to nerve injury.
doi:10.1186/1744-8069-7-1
PMCID: PMC3022745  PMID: 21205324
16.  Repeatability of Response to Asthma Medications 
Background
Pharmacogenetic studies of drug response in asthma assume that patients respond consistently to a treatment but that treatment response varies across patients, however, no formal studies have demonstrated this.
Objective
To determine the repeatability of commonly used outcomes for treatment response to asthma medications: bronchodilator response, forced expiratory volume in 1 second (FEV1), and provocative concentration of methacholine producing a 20% decline in FEV1 (PC20).
Methods
The Childhood Asthma Management Program (CAMP) was a multi-center clinical trial of children randomized to receiving budesonide, nedocromil, or placebo. We determined the intraclass correlation coefficient (ICC) for each outcome over repeated visits over four years in CAMP using mixed effects regression models. We adjusted for the covariates: age, race/ethnicity, height, family income, parental education, and symptom score. We incorporated each outcome for each child as repeated outcome measurements and stratified by treatment group.
Results
The ICC for bronchodilator response was 0.31 in the budesonide group, 0.35 in the nedocromil group, and 0.40 in the placebo group, after adjusting for covariates. The ICC for FEV1 was 0.71 in the budesonide group, 0.60 in the nedocromil group, and 0.69 in the placebo group, after adjusting for covariates. The ICC for PC20 was 0.67 in the budesonide and placebo groups and 0.73 in the nedocromil group, after adjusting for covariates.
Conclusion
The within treatment group repeatability of FEV1 and PC20 are high; thus these phenotypes are heritable. FEV1 and PC20 may be better phenotypes than bronchodilator response for studies of treatment response in asthma.
doi:10.1016/j.jaci.2008.10.015
PMCID: PMC2980870  PMID: 19064281
asthma; drug response; heritability; bronchodilator; pharmacogenetics
17.  Asthma-susceptibility variants identified using probands in case-control and family-based analyses 
BMC Medical Genetics  2010;11:122.
Background
Asthma is a chronic respiratory disease whose genetic basis has been explored for over two decades, most recently via genome-wide association studies. We sought to find asthma-susceptibility variants by using probands from a single population in both family-based and case-control association designs.
Methods
We used probands from the Childhood Asthma Management Program (CAMP) in two primary genome-wide association study designs: (1) probands were combined with publicly available population controls in a case-control design, and (2) probands and their parents were used in a family-based design. We followed a two-stage replication process utilizing three independent populations to validate our primary findings.
Results
We found that single nucleotide polymorphisms with similar case-control and family-based association results were more likely to replicate in the independent populations, than those with the smallest p-values in either the case-control or family-based design alone. The single nucleotide polymorphism that showed the strongest evidence for association to asthma was rs17572584, which replicated in 2/3 independent populations with an overall p-value among replication populations of 3.5E-05. This variant is near a gene that encodes an enzyme that has been implicated to act coordinately with modulators of Th2 cell differentiation and is expressed in human lung.
Conclusions
Our results suggest that using probands from family-based studies in case-control designs, and combining results of both family-based and case-control approaches, may be a way to augment our ability to find SNPs associated with asthma and other complex diseases.
doi:10.1186/1471-2350-11-122
PMCID: PMC2927535  PMID: 20698975
18.  Predicting response to short-acting bronchodilator medication using Bayesian networks 
Pharmacogenomics  2009;10(9):1393-1412.
Aims
Bronchodilator response tests measure the effect of β2-agonists, the most commonly used short-acting reliever drugs for asthma. We sought to relate candidate gene SNP data with bronchodilator response and measure the predictive accuracy of a model constructed with genetic variants.
Materials & methods
Bayesian networks, multivariate models that are able to account for simultaneous associations and interactions among variables, were used to create a predictive model of bronchodilator response using candidate gene SNP data from 308 Childhood Asthma Management Program Caucasian subjects.
Results
The model found that 15 SNPs in 15 genes predict bronchodilator response with fair accuracy, as established by a fivefold cross-validation area under the receiver-operating characteristic curve of 0.75 (standard error: 0.03).
Conclusion
Bayesian networks are an attractive approach to analyze large-scale pharmacogenetic SNP data because of their ability to automatically learn complex models that can be used for the prediction and discovery of novel biological hypotheses.
doi:10.2217/pgs.09.93
PMCID: PMC2804237  PMID: 19761364
asthma; Bayesian networks; β2-agonists; bronchodilator response; prediction
19.  INSIG2 is Associated with Lower Gain in Weight-for-Length Between Birth and Age 6 Months 
Researchers have described the association of a common DNA polymorphism, rs7566605, near INSIG2 (insulin-induced gene 2) with obesity in multiple independent populations that include subjects ages 11–60 years.1 To our knowledge, no studies have examined the association of this polymorphism with weight status during early childhood. We explored the association of the rs7566605 polymorphism with weight-for-length among 319 children at 6 months and 3 years participating in Project Viva, a pre-birth cohort study. In contrast to studies of older individuals, CC homozygosity was associated with lower gain in weight-for-length z-score between birth and age 6 months than GG homozygosity or GC heterozygosity. At age 3, we did not find an association. The association of INSIG2 gene with obesity may change direction with age.
PMCID: PMC2846639  PMID: 20354568
INSIG2; obesity; infancy; weight-for-length
20.  Asthma self-assessment in a Medicaid population 
BMC Public Health  2009;9:244.
Background
Self-assessment of symptoms by patients with chronic conditions is an important element of disease management. A recent study in a commercially-insured population found that patients who received automated telephone calls for asthma self-assessment felt they benefitted from the calls. Few studies have evaluated the effectiveness of disease self-assessment in Medicaid populations. The goals of this study were to: (1) assess the feasibility of asthma self-assessment in a population predominantly insured by Medicaid, (2) study whether adding a gift card incentive increased completion of the self-assessment survey, and (3) evaluate how the self-assessment affected processes and outcomes of care.
Methods
We studied adults and children aged 4 years and older who were insured by a Medicaid-focused managed care organization (MCO) in a pre- and post-intervention study. During the pre-incentive period, patients with computerized utilization data that met specific criteria for problematic asthma control were mailed the Asthma Control Test (ACT), a self-assessment survey, and asked to return it to the MCO. During the intervention period, patients were offered a $20 gift card for returning the completed ACT to the MCO. To evaluate clinical outcomes, we used computerized claims data to assess the number of hospitalization visits and emergency department visits experienced in the 3 months after receiving the ACT. To evaluate whether the self-management intervention improved processes of care, we conducted telephone interviews with patients who returned or did not return the ACT by mail.
Results
During the pre-incentive period, 1183 patients were identified as having problems with asthma control; 25 (2.0%) of these returned the ACT to the MCO. In contrast, during the incentive period, 1612 patients were identified as having problems with asthma control and 87 (5.4%) of these returned the ACT to the MCO (p < 0.0001). Of all 95 ACTs that were returned, 87% had a score of 19 or less, which suggested poor asthma control.
During the 3 months after they received the ACT, patients who completed it had similar numbers of outpatient visits, emergency department visits, and hospitalizations for asthma as patients who did not complete the ACT. We completed interviews with 95 patients, including 28 who had completed the ACT and 67 who had not. Based on an ACT administered at the time of the interview, patients who had previously returned the ACT to the MCO had asthma control similar to those who had not (mean scores of 14.2 vs. 14.6, p = 0.70). Patients had similar rates of contacting their providers within the past 2 months whether they had completed the mailed ACT or not (71% vs. 76%, p = 0.57).
Conclusion
Mailing asthma self-assessment surveys to patients with poorly controlled asthma was not associated with better asthma-associated outcomes or processes of care in the Medicaid population studied. Adding a gift card incentive did not meaningfully increase response rates. Asthma disease management programs for Medicaid populations will most likely need to involve alternative strategies for engaging patients and their providers in managing their conditions.
doi:10.1186/1471-2458-9-244
PMCID: PMC2716341  PMID: 19607719
21.  INSIG2 is Associated with Lower Gain in Weight-for-Length Between Birth and Age 6 Months 
Researchers have described the association of a common DNA polymorphism, rs7566605, near INSIG2 (insulin-induced gene 2) with obesity in multiple independent populations that include subjects ages 11–60 years.1 To our knowledge, no studies have examined the association of this polymorphism with weight status during early childhood. We explored the association of the rs7566605 polymorphism with weight-for-length among 319 children at 6 months and 3 years participating in Project Viva, a pre-birth cohort study. In contrast to studies of older individuals, CC homozygosity was associated with lower gain in weight-for-length z-score between birth and age 6 months than GG homozygosity or GC heterozygosity. At age 3, we did not find an association. The association of INSIG2 gene with obesity may change direction with age.
PMCID: PMC2846639  PMID: 20354568
INSIG2; obesity; infancy; weight-for-length

Results 1-21 (21)